Development of a CNP related drug as a new treatment for hypertension and arteriosclerosis.

开发 CNP 相关药物作为高血压和动脉硬化的新治疗方法。

基本信息

批准号：
05557051
负责人：
NAKAO Kazuwa
金额：
$ 6.34万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

项目摘要

CNP,the third member of the natriuretic peptide family, has been considered to act as a neuropeptide. We observed presence of three natriuretic peptides in human cerebrospinal fluid and that CNP was the major natriuretic peptide. We discovered that CNP was present mainly as CNP-53 in peripheral tissues and that CNP mRNA was present in ileum-jejum, testis, thymus, adrenal gland and submaxillary gland. We also discovered that CNP is produced and gecreted by the endothelial cells. The endothelinl secretion of CNP was regulated by interleukin Ialpha, Ibeta, transforming growth factor beta, tumor necrosis factor-alpha and also by lipopolysaccharide. Furthermore, CNP was detected in plasma of septic shock patients. The treatment of vascular smooth muscle cells with ANP,BNP of CNP decreased the C-receptor density and the rank order of potency for this downregulation was CNP>ANP>BNP.The rank order was the same as that for cGMP production and 8-bromo-cGMP significartly decreased the C-receptor density and its mRNA expression in vascular smooth muscle cells. These results suggest that the downregulation of the C-receptor is induced by the activation of the GC-B receptor/cGMP pathway. We also found that the beta2-adrenergic receptor stimulation downregulates the C-receptor through the decrease in the transcriptional rate of the C-receptor gene. The mouse CNP gene is composed of at least two exons and one intron. Mouse prepro CNP comprises 126 amimo acids and its C-terminal 22-residue peptide is identical to human CNP.The 5'-flanking region of the mouse CNP gene contains a characteristic array of cis-acting regulatory elements and a dinucleotide CA repeat.

CNP是亚位尿肽家族的第三个成员，被认为是神经肽。我们观察到人脑脊髓液中存在三种亚钠肽，并且CNP是主要的脂肪尿肽。我们发现CNP主要以CNP-53的形式存在于外周组织中，并且CNP mRNA存在于Ileum-Jejum，睾丸，胸腺，胸腺，肾上腺和超质腺体中。我们还发现，CNP是由内皮细胞产生和固定的。 CNP的内皮分泌由白介素ialpha，Ibeta，转化生长因子β，肿瘤坏死因子-Alpha以及脂多糖调节。此外，在败血性休克患者的血浆中检测到CNP。用ANP治疗血管平滑肌细胞，CNP的BNP降低了C受体密度，这种下调的效力等级顺序为CNP> ANP> ANP> BNP。等级顺序与CGMP产生和8-Bromo的等级顺序相同-CGMP显着降低了C受体密度及其在血管平滑肌细胞中的mRNA表达。这些结果表明，C受体的下调是由GC-B受体/CGMP途径的激活引起的。我们还发现，β2-肾上腺素能受体刺激通过c受体基因的转录速率降低来下调C受体。小鼠CNP基因由至少两个外显子和一个内含子组成。小鼠前CNP包含126个Amimo酸，其C末端22个残留肽与人CNP相同。小鼠CNP基因的5'-乘区域包含一系列特征性的调控元件和dincleotide ca重复。